This invention relates to compounds that are specifically targeted for tumor cells and tumor-associated blood vessels and that can deliver various effector molecules to these sites.
Certain proteins are known to increase the permeability of blood vessels. One such protein factor, known as vascular permeability factor (VPF), is a highly conserved 34-42 kD protein secreted by many tumor cells that has been isolated from serum-free culture medium of carcinoma and sarcoma tumor cells and from tumor ascites fluids. Antibodies directed against VPF have also been created. Dvorak et al., U.S. Pat. No. 4,456,550, which is incorporated herein by reference, describes both the isolation of VPF and the creation of antibodies against VPF.
VPF is now known to be the same molecule as vascular endothelial growth factor (VEGF), as evidenced by the following points of identity: (1) molecular weight and NH.sub.2 - terminal amino acid sequence of the purified proteins (Ferrara, N., et al., Biochem. Biophys. Res. Comm., 161:851-858 (1989); Connolly, D. T., et al., J. Biol. Chem., 264: 20017-20024 (1989); Senger, et al., Cancer Res., 50: 1774-1778 (1990)), (2) cDNA cloning and sequencing (Leung, D. W., et al., Science, 246:1306-1309 (1989); Keck, P. J., et al., Science, 246:1309-1312 (1989)), and (3) probable identical biological activities (Connolly, D. T., et al., J. Clin. Invest., 84: 1470-1478 (1989)).
Alternative forms of VPF/VEGF have been identified, and it has been determined that these forms arise as a consequence of alternative mRNA splicing of transcripts from the VPF/VEGF gene. Tischer, E., et al., J. Biol. Chem., 266:11947-11954 (1991). As used herein, "VPF" encompasses all such alternative forms.